Diabetes is a metabolic disorder with recurrent or persistent hyperglycemia. Abnormal levels of blood glucose can lead to some serious and long-term complications, including cardiovascular disease, chronic renal failure, retinal damage, nerve damage, microvascular damage and obesity.
In the early stages of diabetes treatment, control of diet and exercise therapies are the preferred method for controlling blood glucose. When control of blood glucose is difficult to achieve with these methods, insulin or oral hypoglycemic drugs are needed for the treatment. There have been a variety of hypoglycemic drugs used currently in clinical treatment, including biguanide compounds, sulfonylurea compounds, insulin resistance improving agents, α-glucosidase inhibitors and so on. However, each of these drugs has various toxic effects and side effects, and is unable to meet the needs of long-term treatment. For example, biguanide compounds can cause lactic acidosis; sulfonylurea compounds can lead to hypoglycemia; insulin resistance improving agents can induce edema and heart failure, and α-glucosidase inhibitors can cause abdominal pain, distention, diarrhea and other symptoms. Because of the above situation, it is necessary to develop safer and more effective novel anti-diabetic drugs to meet the needs of diabetes treatment.
Studies have found that the regulation of cells regarding the process of glucose transport is mainly achieved by promoting the two protein family members of glucose transporter protein (GLUTs) (passive transport) and sodium-dependent glucose co-transporter protein (SGLTs) (active transport). SGLTs family members with glucose transporter function are mainly distributed in the intestine and the proximal tubule of the kidney and so on. Accordingly, it can be inferred that the SGLTs family members play a key role in glucose absorption in the intestine and glucose reuptake in the kidney, and they will become one of the ideal potential targets for treating diabetes.
In particular, SLGT-1 protein is one of the family members that is mainly distributed in the intestinal mucosal cells of the small intestine, with little expression in cardiac muscle and the kidney. It is mainly collaborative with GLUTs proteins to regulate glucose absorption in the intestine. Another one of the family members is SGLT-2, which is mainly responsible for regulating glucose reuptake in the kidneys due to its high level of expression in the kidneys, i.e., when glucose in urine passes through the glomerulus, it can actively attach to the epithelial cells of the renal tubule and be transported into the cells and recycled. During this process, SGLT-2 is responsible for 90% of reabsorption, and the remaining 10% of reabsorption is completed by SGLT-1. The theory of SGLT-2 as a major transport protein has been further confirmed in animal tests. SGLT-2 mRNA levels in rat renal cortex cells are reduced by specific SGLT-2 antisense oligonucleotides, thereby significantly inhibiting the reuptake of rat renal glucose. Based on these findings, it can be inferred that if a SGLTs (SGLT-1/SGLT-2) protein inhibitor is developed, through the regulation of its glucose transport function, it is possible to control intestinal absorption of glucose on the one hand, and on the other hand, to inhibit the reuptake of renal glucose and enhance discharge of glucose from the urine, thereby achieving a more systematic hypoglycemic effect. Therefore, a dual action inhibitor can be an ideal drug for treating diabetes.
Additionally, studies also found that SGLTs protein inhibitors can be useful for the treatment of diabetes-related complications, such as retinopathy, neuropathy, nephropathy, insulin resistance caused by glucose metabolism disorders, hyperinsulinemia, hyperlipidemia, obesity and so on. SGLTs protein inhibitors can be combined with the existing therapeutic agents, such as sulfonamides, thiazolidinediones, metformin, and insulin, etc. Without affecting efficacy, the dosage of drugs can be reduced to avoid or reduce the occurrence of adverse effects, thereby improving the adaptability of the patient to the treatment.
In summary, as a novel drug for treating diabetes, SGLTs protein inhibitor has good development prospects. Therefore, there is an urgent need to develop an effective compound that is safe and has good pharmacokinetic properties for the treatment of diabetes and related metabolic disorders.